Pharmacokinetics of pimecrolimus in
infants
Initial safety concerns were related to the potential systemic
absorption of pimecrolimus. However, evidence from experiments in
minipigs showed that the systemic bioavailability of pimecrolimus was
transient and negligible, making the risk for systemic side effects not
relevant (59). Furthermore, the penetration and permeation profile of
pimecrolimus was superior compared to other treatments for AD. Whereas
drug concentrations of pimecrolimus in human skin were of the same order
of magnitude as tacrolimus and TCS, permeation was 9-10 and 70-110 fold
lower than tacrolimus and TCS, respectively, predicting lower systemic
exposure (60). The pharmacokinetic (PK) profile of pimecrolimus was
evaluated in six studies, which enrolled a total of 41 infants treated
with pimecrolimus for 3 weeks (Table 2) . Pimecrolimus blood
concentrations were below the limit of quantification (LoQ) in the
majority of samples, which was either 0.1 or 0.5 ng/mL, depending on the
assay used (61-65). In the remaining blood samples, the blood
concentration of pimecrolimus was below 2 ng/mL, with some exceptional
outliers that were just above this limit. One study evaluated blood
samples of infants aged between 5.7-11.9 months over a 1-year period of
intermittent pimecrolimus treatment (63). Importantly, this study found
no accumulation of pimecrolimus in infants with moderate-to-severe AD,
consistently showing minimal systemic exposure even on the long-term.
The impact of the total body surface area (TBSA) affected was also found
to be minimal, and the difference between patients with 90% and 10% of
TBSA affected was not greater than 0.74 ng/mL (62). These findings were
also supported by another study, which enrolled infants with a maximum
TBSA affected of 92%, but systemic pimecrolimus concentrations remained
below 2.26 ng/mL in all infants after 3 weeks of treatment (65). These
concentrations are far below the maximum blood concentration (54.5
ng/mL) observed in adult patients with psoriasis treated orally with 30
mg twice daily of pimecrolimus for 4 weeks, a dose that was also
well-tolerated in these patients (62). An analysis of pimecrolimus blood
concentrations in infants compared to older children (>24
months of age) demonstrated that infants were not a higher risk for
systemic exposure of pimecrolimus, and that blood concentrations of
pimecrolimus remained below the LoQ (i.e. <0.5 ng/mL) in the
majority of patients, irrespective of age (66). Overall, the favorable
penetration and permeation profile of pimecrolimus seen in minipigs
together with the minimal systemic exposure found in the PK studies
support that use of pimecrolimus in infants is safe, regardless of the
TBSA affected and duration of treatment.